Fluoromethanesulfonic acid derivatives

ABSTRACT

The compounds disclosed are the amphoteric compound 2-hydroxy-5(1-hydroxy-2-(4&#39;&#39; -methoxyphenethylamino)propyl)fluoromethanesulfonanilide and its acid addition and metal salts. These compounds have physiological activity, including significant insecticidal activity evinced as activity against mosquito larvae.

United States Patent [m Robertson Sept. 18, 1973 [54]FLUOROMETHANESULFONIC ACID 3,644,520 2/l972 Hartley et al. 260/556 ADERIVATIVES [75] Inventor: Jerry E. Robertson, North Oaks, primaryExamine, Hemy m Assistant Examiner-S. D. Winters [73] Assignee: RikerLaboratories, Inc., Northridge, AtmmeyAleXandeT, Sell Stem DelahumCalif.

[22] Filed: Sept. 27, 1971 21 Appl. No.: 184,229 [57] ABSTRACT Thecompounds disclosed are the amphoteric com- [52] US. Cl. 260/556 A,260/556 F, 260/575, ound 2.h d -5-[1-h d -2-(4' 424/321methoxyphenethylamino)propyl]- [51] Int. Cl. C071: 143/74fluommethanesulfonanilide and its acid addition and [58] Field of Search260/556 F, 556 A t l alt These compounds have physiological activity,including significant insecticidal activity evinced as [56] ReferencesCited activity against mosquito larvae.

UNITED STATES PATENTS 9/1967 Larsen et al. 260/556 A 6 Claims, NoDrawings 1 FLUo'RiiMETIIA'NEsU'LFoNIc ACID DERIVATIVES BACKGROUND or THEINVENTION Substituted methanesulfonanilides are known, and are broadlydisclosed in the prior art, as, for example, in U.S. Pat. Nos. 3,341,584and 3,478,149. The compounds disclosed in these patents are described ashaving physiological activity, but this did not include insecticidalactivity. A compound closely related to the base of the presentinvention, 2-hydroxy-5-[ l-hydroxy-2- (4'-methoxyphenethylamino)propyl]-methanesulfonanilide, described in the said patents, has physiologicalactivity but is inactive towards mosquito larvae. The compound and itssalts which are described and claimed herein have strong activity asmosquito larvicides, as well as other useful physiological activity,e.g., bronchodilator activity in the mammalian organism.

cess for the preparation of the compounds ofthe inven- 25 tion. Thisinvention also relates to novel intermediates useful for the preparationof the final product compounds of the invention.-

The intermediates and final product compounds of the present inventionare preparedv using the reaction 30 sequence illustrated belowstartingwith the known compounds 3-arnino-,4-benzyloxypropiophenone and'fluoromethanesulfonyl chloride.

compound are readily converted to the free base. This can be done, forexample, by neutralizing a solution of the salt in water with anequimolar solution of sodium bicarbonate and azeotroping off the waterwith benzene. The residue is extracted with acetone, then the acetone isevaporated to give 2-hydroxy,-5-[ l-hydroxy-2-(4Gmethoxyphenethylamino)propyl]fluoromethanesulfonanilide as a whitesolid.

It will be apparent to those skilled in the art that the final productcompound of the invention (and its salts) contains two asymmetric carbonatoms, and two racemic modifications of the product exist, each of whichconsists of a pair of enantiomorphic forms. All of these fourenantimor'phic forms (and their salts) are included within the scope ofthis invention.

The basic compound of this invention is an amphoteric substance, formingsalts with both acids and bases. These salts are considered part of thisinvention. Each of the salts has a utility, since it may be converted tothe compound of the invention and the compound of the invention may beconverted to other salts. Acid addition salts with optically activeacids such as d-camphorsulfonic acid are useful for resolution of theenantiomorphic pairs. Preferred salts are those with pharmaceuticallyacceptable acids and metals.

Examples of acid addition salts include the'hydrochloride, hydrobromide,phosphate, sulfate, acetate, propionate, nitrate, gluconate, succinate,mucate, methanesulfonate, oxalate and the like. Examples of metal saltsare the lithium, sodium and potassium (alkali metal) salts.

Th'e'metal salts may be formed by reaction of the Nns'o'renm NIH} iCISOZCHZF 0 liomcm Step (I) NH S 02CH2 F l) NIhCIIzCHz-@- C) -oH=0 aBrominate l2 Acld Jz-orrcm St p (3) Step (2) NI'I S O1CH2 F -$(?HGHI NHJHzCHI@ Acid NH s 010mm 1) Reduction 7 H0 2) Debenzylatlon I /C H,

OHO

The product isolated from step (4)'of the reaction secompound of theinvention with equimolar quantities quence shown is the acid additionsalt of the base 2-. 'of metal hydroxides, alkoxides, carbonates and thelike,

hydroxy-5-[ l-hydroxy-2-(4'-methoxyphenethylamino)propyl]fluoromethanesulfonanilide. Acid additionsalts of the novel amphoteric as will be apparent to those skilled inthe art.

The infrared spectrum of the free base indicates that it exists as theinternal salt of the formula:

Specific illustration of the process step in the reaction sequence shownis provided by the following example. All parts are by weight unlessotherwise specified. Analyses are shown in percentages.

Example 1 To a stirred solution of 3'-amino-4'-benzyloxypropiophenone(80 g., 0.31 mole), dimethylaniline (41.2 g., 0.34 mole) and chloroform(400 ml.) is added dropwise fluoromethanesulfonyl chloride (41.2 g.,0.31 mole) over a peirod of 30 minutes. A slight exotherm results. Thesolution is stirred for about 64 hours. The solution is washed withdilute hydrochloric acid, washed with water and dried over magnesiumsulfate. The solvent is evaporated in vacuo, yielding a yellowish solid.Recrystallization from ethanol gives 2-benzyloxy-5-pripionylfluoromethanesulfonanilide, m.p. l l-l 1 1 C.

Analysis:

Calculated for C,-,H, FNO,S: C, 58.1; H, 5.2

Found: C, 58.6; H, 5.3.

Cupric bromide (84 g., 0.375 mole) in ethyl acetate (300 ml.) is heatedto reflux temperature and stirred while refluxing for two hours.2-Benzyloxy-5- propionylfuloromethanesulfonanilide (82 g., 0.234 mole)is added, dissolved in ethyl acetate 150 ml.) and chloroform (150 ml.).The resulting mixture is stirred at room temperature for six hours. Thereaction mixture is filtered, the filtrate is treated with decolorizingcharcoal and theresulting solution is evaporated to yield an oil. Theoil is taken up in ethanol, treated with decolorizing charcoal anddiluted with water, but upon cooling an oil is obtained. Evaporation ofthe solvent in vacuo gives an oil. The oil is taken up in isopropanol,treated with decolorizing charcoal and filtered. Seed crystals are addedwhile cooling, and a solid is obtained. The solid is againrecrystallized from isopropanol, triturating with benzene. Solid2-benzyloxy-5-(2- bromopropionyl)fluoromethanesulfonanilide, m.p. 76-81C. is obtained. A proton magnetic spectrum shows that this solidcontains about 45 percent benzene of crystallization.

Aluminum chloride (0.025 g.) and 2-benzyloxy-5-propionylfluoromethanesulfonanilide (8.8 g., 0.025 mole) are suspendedin diethyl ether (50 ml.) and the mixture is stirred vigorously at roomtemperature while adding bromine (4.0 g., 0.024 mole) dropwise overtwenty minutes. The orange-red mixture is stirred one hour at roomtemperature. The mixture is filtered and diethyl ether (75 ml.) isadded. The filtrate is washed in succession with water, percent sodiumbicarbonatev solution and saturated sodium chloride solution. Thesolution is then dried over magnesium sulfate and the solvent evaporatedin vacuo to give a yellow-orange oil which slowly crystallizes. Theproduct, 2-benzyloxy-5- (2-bromopropionyl)fluoromethanesulfonanilide is'a white solid, m.p. 7779 C., after recrystallizing three times fromtrichloroethylene with treatment with decolorizing charcoal. Analysis:

Calculated for C H ,BrFNO,S: C, 47.5; H, 4.0; N,

3.25 Found: C, 47.9; H, 4.0; N, 3.1.

To a solution of 4-methoxyphenethylamine (25 g., 0.165 mole) in methanol(25 ml.) cooled to 0 to 5 C. is added2-benzyloxy-5-(2-bromopropionyl)fluoromethanesulfonanilide (15 g., 0.035mole) in small portions over a period of 1.5 hours. The mixture isstirred for an additional 2 hours. The pH is adjusted to about 1 by theaddition of 15 ml. of concentrated hydrochloric acid. An additional 25ml. of methanol is added, and the mixture is stirred one-half hour. Themixture is filtered and the filtrate is concentrated to one-half of itsvolume. The resulting solid is separated by filtration and examined byinfrared spectroscopy, showing it to be chiefly 4'-methoxyphenethylaminehydrochloride. The filtrate is diluted with diethyl ether, and the solidis separated by filtration and examined by infrared spectroscopy. Astrong carbonyl absorption is present, indicating the desired product.This solid is extracted twice with hot ethanol, leaving solid2-benzyloxy-5-[2-(4-methoxyphenethylamino)propionyl]fluoromethanesulfonanilidehydrochloride, m.p. 2l2-215 C.

To a solution of 2-benzyloxy-5-[2-(4-methoxyphenethylamino)propionyl]fluoromethanesulfonanilide hydrochloride(3.6 g., 0.0067 mole) in ethanol (100 ml.) is added 0.5 g. of palladiumon carbon, and the mixture is hydrogenated at room temperature in a Parrhydrogenator (maximum hydrogen pressure about 50 psi) for 12 hours.

The reaction mixture is treated with decolorizing charcoal, filtered andthe solvent removed by evaporation in vacuo. The white solid isdissolved in isopropanol, treated with decolorizing charcoal and,following the addition of diethyl ether, crystallizes slowly formingwhite, solid 2-hydroxy-5-[ l-hydroxy-2-(4methoxyphenethylamino)propyl1fluoromethanesulfonanilide hydrochloride,m.p. l-180 C.

Analysis:

Calculated for C H ClFN O Sz C, 50.1; H, 5.8; N,

6.2 Found: C, 50.5; H, 5.7; N, 6.1.

A sample of 2-hydroxy-5-[ l-hydroxy-2-(4-methoxyphenethylamino)propyl]fluoromethanesulfonanilide hydrochloride(1.12 g., 0.025 mole) is dissolved in water (20 ml.). A solution ofsodium bicarbonate (0.21 g., 0.025 mole) in a minimum amount of water isadded with stirring and the mixture is evaporated in vacuo. Benzene isadded and the mixture again evaporated thrice'to remove traces of water.The residue is triturated with acetone and filtered. The filtrate isevaporated to dryness yielding 2-hydroxy-5-[1-hydroxy-2-(4'-methoxyphenethylamino)propyl]- fluoromethanesulfonanilideas a foamy white crystalline solid, crude m.p. 60-75 C. Its structure iscon- 1 firmed by nuclear magnetic resonance and infrared spectralmeasurement.

In order to determine the mosquito larvicidal activity2-hydroxy-5-(1-hydroxy-2-[4'-methoxyphenethylamino)propyllfluoromethanesulfonanilide hydrochloridethe following'test was run. Aedes aegypti mosquito eggs are hatched indistilled water. The larvae are fed on finely ground dog chow. Afterfive to seven days, the larvae are ready for use. Two replicates areused for each concentration. A stock solution of compound is made bydissolving 0.236 g. of compound in acetone (15 ml.) to give aconcentration of 20,000 ppm. A sample of 1.25 ml. of this solution ismixed with 48.75 ml. of water to provide a 500 ppm solution. Measuredamounts of this solution are added to vials containing to mosquitolarvae to give concentrations of 200, 100 and 50 parts per millionrespectively. Control vials with larvae are also maintained in waterwithout added larvicide. After 3 hours and 4 hours mortality data aretaken. The results are shown in Table 1.

TABLE 1 Concentration Compound (in ppm) 3 hours 4.5 hours Compound ofthe example 200 87 100 100 97 100 50 60 82 Control 0 0 The compounds ofthe invention have bronchodilator activity which is manifested in astandard test for such activity (isolated tracheal spiral). The testsperformed heretofore have indicated that the mechanism of bronchodilatoractivity may be different from that of 2- hydroxy-S-ll-hydroxy-2-(4'-mcthoxyphenethylamino)propyl]methanesulfonanilide. The intravenoustoxicity of the compounds of the invention (as the hydrochloride) alsoappears to be significantly lower.

An alternative, and presently preferred, process is illustrated inExample 2 below. The preferred proces provides improved yields. Thisprocess requires that the acidic sulfon-amido nitrogen atom of theintermediate compound 2-benzyloxy-5-propionylfluoromethanesulfonanilidebe blocked by reaction with benzyl chloride to form the benzylderivative. This blocked" compound is carried through the remainder ofthe sequence described on page 2, which is more specifically illustratedas follows:

Example 2 To a stirred solution of potassium carbonate (2.07 g., 15mmole) and sodium iodide (0.10 g.) in water (10 ml.) is added2-benzyloxy-5-propionylfluoromethanesulfonanilide (3.51 g., 10 mmoles),prepared as described in Example 1, and benzyl chloride (1.52 g., 12mmoles) in glyme (15 ml.). The mixture is heated to its refluxtemperature and maintained at reflux for one day, cooled to roomtemperature and evaporated under vacuum. The residue is extracted withdichloromethane, then the organic extract is washed with water, 10percent sodium hydroxide solution then water again. The organic solutionis then evaporated under vacuum to an oil which solidifies slowly.Recrystallization from ethanol and treatment with decolorizing charcoal(twice) provides ivory-colored needles (2.6 g., 59 percent) ofN-benzy1-2-benzyloxy-5 propionylfluoromethanesulfonanilide, m.p. 90-91.5C. Analysis:

Calculated for C ,,H FNO.,S: C, 65.3; H, 5.5; N, 3.2

Found: C, 65.0; H, 5.6; N, 3.1.

To a refluxing solution of cupric bromide (4.24 g., 19 mmoles) in ethylacetate (15 ml.) is added dropwise a solution ofN-benzyl-2-benzyloxy-S-propionylfluoromethanesulfonanilide (4.4 g., 10mmoles) in chloroform (15 ml.). The mixture is maintained at reflux forsix hours, cooled and filtered. The filtrate is diluted with chloroform(30 ml.), washed with water, 5 percent sodium bicarbonate solution, thenwater again.

crystals After drying, the organic solution is evaporated under vacuum.The crude product (7.8 g.) is recrystallized from ethanol with treatmentwith decolorizing charcoal (twice) to provide 1.3 g. (25 percent) ofN-benzyl-Z- benzyloxy-S-(2-bromopropionyl)fluoromethanesulfonanilide,m.p. 108-109 0. Analysis:

Calculated for C H BrFNO S: C, 55.4; H, 4.5; N,

2.7 Found: C, 55.7; H, 4.6; N, 2.5.

To a stirred solution of 2-(4-methoxyphenyl)ethylamine (6.05 g., 40mmoles) in acetonitrile (40 ml.) is added dropwise a solution ofN-benzyl-2-benzyloxy-5- (2-bromopropionyl)fluoromethanesulfonanilide10.4

g., 20 mmoles) in acetonitrile (40 ml.). The reaction mixture is stirredfor an additional 1.5 hours, then poured into diethyl ether (750 ml.).The mixture is filtered, then the filtrate is evaporated under vacuum.The residue from the evaporation is dissolved in dichloromethane, thesolution is washed with water, dried, then partially evaporated undervacuum to a volume of 30 to 40 ml. This solution is added to 750 ml. ofdiethyl ether saturated with hydrogen chloride. The crude product (9.1g., 73 percent) separates on cooling, is isolated by filtration,dissolved in acetonitrile (120 ml.), filtered, the solution warmed on asteam bath, then cooled. An ivory-white solid (6.6 g., 53 percent)precipitates and is isolated by filtration and dried. The infraredspectrum of the product is consistent with that expected forN-benzyl-2-benzyloxy-5-[2-(4'- methoxyphenethylamino)-propionyl]fluorornethanesulfonanilide hydrochloride, m.p. 213-216 C.

A solution of N-benzyl-2-benzyloxy-5-[2-(4'-methoxyphenethylamino)propionyllfluoromethanesulfonanilide hydrochloride(23 g., 37 mmoles) in ethanolzwater (:10, 1,200 ml.) is obtained bywanning the mixture. After cooling to 25 C. the solution is added to apaste of 2.0 g. 10 percent palladium on charcoal in water in ahydrogenation bottle. The mixture is hydrogenated for 16.5 hours in aParr apparatus at about 40 p.s.i. of hydrogen. The mixture is carefullyand thoroughly filtered, and the filtrate is evaporated under vacuum.The crude product 17 g., percent) is dried by azeotropic distillationwith benzene, then dissolved in acetonitrile and treated twice withdecolorizing charcoal. Slow cooling provides the desired product aswhite crystals after filtration and drying (13 g., 80 percent). Anotherrecrystallization provides white of Z-hydroxy-S-I l-hydroxy-2-(4-methoxyphenethylamino)propyllfluoromethanesulfonanilide hydrochloride,m.p. -183 C.

Analysis:

Calculated for C,,,H FN O S'HCl: C, 50.8; H, 5.8; N,

6.2 Found: C, 50.9; H, 5.6; N, 6.2. What is claimed is: l. The compound2-hydroxy-5-[l hydroxy-2-(4'-methoxyphenethylamino)propyllfluoromethanesulfonanilide and its acidaddition and metal salts. 2. Acid addition salts according to claim 1.3. A hydrochloride salt according to claim 2. 4. The compound2-benzyloxy-5-propionylfluoromethanesulfonanilide.

5. The compound 2-benzyloxy-5-(2-bromopropionyl)fluoromethanesulfonanilide.

6. The compound 2-benzyloxy-5-[2-(4'-methoxyphenethylamino)-propionyl]fluoromethanesulfonanilidehydrochloride.

- a :r x

2. Acid addition salts according to claim
 1. 3. A hydrochloride saltaccording to claim
 2. 4. The compound2-benzyloxy-5-propionylfluoromethanesulfonanilide.
 5. The compound2-benzyloxy-5-(2-bromopropionyl)fluoromethanesulfonanilide.
 6. Thecompound 2-benzyloxy-5-(2-(4''-methoxyphenethylamino)-propionyl)fluoromethanesulfonanilide hydrochloride.